Src Homology 2 (SH2) domains are small modular domains found within a great number of proteins involved in different signaling pathways. They are able to bind specific motifs containing a phopshorylated tyrosine residue, propagating the signal downstream promoting protein-protein interaction and/or modifying enzymatic activities. Different families of SH2 domains may have different binding specifity, which is usually determined by few residues C-terminal with respect to the pY (positions +1, +2 and +3. Non-phosphorylated peptides do not bind to the SH2 domains. At least three different binding motifs are known: pYEEI (Src-family SH2 domains), pY[IV].[VILP] (SH-PTP2, phospholipase C-gamma), pY.[EN] (GRB2). The interaction between SH2 domains and their substrates is however dependent also to cooperative contacts of other surface regions.